PROJECT SUMMARY/ABSTRACT Obesity and diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. This is of increasing concern since the incidence of obesity and insulin resistance is increasing and as many as 1 in 4 Americans are expected to have diabetes by the year 2030. In spite of all the beneficial interventions implemented in patients with diabetes, including tight glucose control, tight blood pressure control, angiotensin converting enzyme inhibition or angiotensin II receptor antagonism, renal disease progresses in most of these patients. Additional treatment modalities that modulate the pathogenesis pathways involved in obesity and diabetic nephropathy are therefore urgently needed to slow the progression of renal disease in patients with obesity and diabetes. Studies from our laboratory indicate that treatment of diabetic mice with a highly active and specific TGR5 agonist prevents the progression of diabetic nephropathy. The beneficial effects of TGR5 activation are associated with stimulation of estrogen-related receptor (ERR) and sirtuin 3 (SIRT3). In this proposal we will test the hypotheses that: 1) TGR5 plays an important role in modulation of kidney disease in diabetes and obesity; 2) TGR5 inhibition accelerates and TGR5 activation prevents obesity and diabetic kidney disease; 3) the beneficial effects of TGR5 are mediated in part through stimulation of ERR. In Specific Aim 1 we will determine the effects of kidney specific TGR5 deletion in kidney disease in obesity and diabetes. In Specific Aim 2 we will determine the effects of kidney specific TGR5 overexpression in kidney disease in obesity and diabetes. In Specific Aim 3 we will determine whether the effect of TGR5 in modulation of kidney disease in obesity and diabetes is dependent on kidney specific ERR activation. Impact: The potential role of TGR5 and ERR in modulating obesity and diabetic renal disease is very novel and will have major implications for the treatment of obesity and diabetes related renal complications. TGR5 and ERR have distinct actions of regulating mitochondrial biogenesis, energy metabolism and energy expenditure: they are therefore quite distinct from other interventions used in treatment of diabetes and its complications where TGR5 can also induce weight loss and prevent obesity.